The influence of sex and gender on pain perception and pain modulatory systems is a research topic of substantial basic science and clinical import. Studies in nonhuman animals and humans indicate greater sensitivity to experimental pain among females. Sex differences in opioid analgesia have also been reported, but are not well characterized in humans. The mechanisms underlying these sex-related differences in pain modulator have not been determined; although, considerable evidence from animals suggests that baseline pain sensitivity and opioid-mediated analgesia vary across the estrous cycle. However, among humans, findings relating pain sensitivity to menstrual cycle phase are inconsistent, and the effects of menstrual cycle phase an opioid analgesia have not been investigated. The studies proposed in this application are designed to further elucidate the nature and mechanisms of sex- related differences in pain modulation by investigating baseline pain sensitivity and opioid analgesia as a function of sex, menstrual cycle phase and oral contraceptive use. Two clinically relevant laboratory pain induction procedures will be used in these studies: 1) temporal summation of thermal pain, and 2) ischemic arm pain. In the proposed study, responses to temporal summation and isochemic procedures will be obtained in females and males before and after administration of morphine, pentazocine and placebo (saline). In addition, two groups of females will be studies: females not taking oral contraceptives (OC) and females taking OC. Both groups of females will participate in each drug condition once during the follicular and once during the luteal phase of the menstrual cycle, and males will participate at similar time intervals. It is hypothesized that: 1) females, regardless of OC status, will exhibit greater baseline pain sensitivity than males, 2) females not taking OC will be more pain sensitive during the luteal compared to the follicular phase of the menstrual cycle, while females taking OC will show no change in pain responses across cycle phase; 3) males will exhibit greater morphine analgesia than females, while females will exhibit greater analgesia to pentazocine than males, and 4) females not taking OC will exhibit less opioid analgesia during the luteal versus the follicular phase of the menstrual cycle, while no menstrual cycle effects on analgesia will emerge for females taking OC.